SUM M A R YGonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. I t is still unknown how puberty in humans, occurring during the early years of the second decade of life, is initiated. 1 The hallmark of puberty is increased secretion of the gonadotropins, luteinizing hormone (LH) and folliclestimulating hormone (FSH), which act in concert to stimulate the gonads to drive sex-hormone secretion and gametogenesis. The production of gonadotropins from pituitary gonadotropic cells is controlled by the pulsatile delivery of GnRH. Inactivating mutations in the genes encoding GNRH1 2 or the GNRH receptor (GNRHR) 3 give rise to normosmic idiopathic hypogonadotropic hypogonadism in humans. 4 However, GnRH neurons lack sex-steroid receptors. This suggests the existence of GnRH-regulating neurons, which would mediate this effect.A major breakthrough in identifying such candidate neurons was the finding that inactivating mutations in genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), the cognate receptor for a hypothalamic peptide, kisspeptin, resulted in pubertal failure. 4,5 More recently, mutations in TAC3 or TACR3 (encoding neurokinin B and its receptor, respectively) were shown to result in the same phenotype. 6 Kisspeptin and neurokinin B are coexpressed, along with dynorphin, in sex-hormone-responsive neurons in the arcuate nucleus (infundibular nucleus in primates), and their coordinated activity appears to regulate GnRH secretion. 7 Gene defects associated with normosmic idiopathic hypogonadotropic hypogonadism have been described in all the neuropeptides and receptors identified as stimulators of GnRH except for the kisspeptin gene (KISS1).Although Kiss1-and Kiss1r-knockout mouse models largely produce phenocopies (i.e., affected noncarriers) of human normosmic idiopathic hypogonadotropic hypogonadism resulting from inactivating mutations of KISS1R, there is evidence of remarkable residual activity of the hypothalamic-pituitary-gonadal axis.
